Before speaking of which patients will likely benefit from GLP-1RA therapy, Rydén briefly summed up what we know about this type of therapy. Incretin-based glucose lowering comes in two options, either by inhibiting the DPP-4 enzyme or giving a GLP-1RA. Various forms of GLP-1RA exist, some short-acting, others long-acting, some are exendin-4 based, and others are more human analogues of the GLP-1 molecule. Effects of the different compounds can vary due to their time of action and their source of origin [29].

In order to know which patients may benefit from this class of drugs, we need to look at the trial populations. The first exendin-based compound tested was lixisenatide, in the ELIXA trial [26]. ELIXA included about 6,000 patients with T2DM, all with a relatively recent coronary syndrome. They were treated with lixisenatide, in addition to ordinary treatment for BP, hypertension, lipids and even other glucose-lowering drugs, compared to placebo added to conventional treatment. Follow-up was around two years. By the end of the study there was not a big difference in HbA1c between the two treatment arms (7.4% with lixisenatide vs. 7.6% with placebo). Likewise, there was no impact on CV mortality, MI, or stroke (HR: 1.02, 95%CI: 0.89-1.17) [26]. Thus, lixisenatide is a safe drug from a CV point of view, but it does not really rescue the patient from future events. The larger EXSCEL study evaluating exenatide was published more recently [28]. It included about 14,700 and lasted about five years. Again, no significant impact on the endpoint of MACE, including MI, stroke or CV mortality was seen stroke (HR: 0.91, 95%CI: 0.83-1.00, P<0.001 for non-inferiority, P=0.06 for superiority).

The human-based GLP-1RAs liraglutide and semaglutide show a different picture. The first one to be reported on is liraglutide (LEADER trial) [13]. Almost 10,000 patients were studied for a follow-up of up to 3.8 years. There was some difference in HbA1c by the end of the trial (~7.7% vs. ~8.0% with liraglutide vs. placebo). And a beneficial effect on the combined CV outcome was seen (HR: 0.87, 95%CI: 0.78-0.97, P<0.001 for non-inferiority, P=0.01 for superiority) [13].

Semaglutide was studied in the SUSTAIN 6 trial [27], in a population of over 3,000 T2DM patients with CVD, with the same principles of study. The difference in HbA1c was somewhat greater (~7.3% vs. 8.3%) than in the other trials. Again there was a substantial reduction in CV endpoints (HR: 0.74, 95%CI: 0.58-0.95, P<0.001 for non-inferiority, P=0.02 for superiority).

Thus, LEADER and SUSTAIN 6 represent two trials that were favorable from a CV point of view and compared to the others. Looking at the LEADER study [13] in a bit more detail, it can be noted that many patients had had an MI or were at very high CV risk. Their BP was fairly well-regulated and about one fifth of the population had heart failure. Diabetes duration was approximately 13 years, and patients were on average 64 years old. The majority were male, which is common in these populations. Both the placebo patients and the liraglutide-treated patients were well treated with glucose-lowering drugs. Recommendations by the trialists stated that glucose should be kept relatively well controlled, and BP as well, and lipids and anti-platelet therapy well practiced. Thus, in this well-treated group, liraglutide therapy beyond standard treatment could further reduce CV events.

Importantly, the results were very consistent. Subgroups in this population, whether based on gender, age, body weight or another patient characteristic, had the same beneficial outcome with very few exceptions. One exception was formed by people who were older and who actually were a little less ill (no CVD yet) than the others. Having insulin from the beginning or during the study did not have any impact on outcomes; the impact of liraglutide was similar in patients with insulin at baseline, and even with insulin instituted during the study.

Annual evaluation of microvascular events in LEADER revealed a decrease of events in liraglutide-treated patients. In addition, HbA1c, body weight, systolic BP, and lipids all show a favorable impact. It is reasonable to assume that all of these factors have importance for the beneficial outcome. But we do not know exactly which of these, or any other impact of GLP-1RA, is the truly important thing.

Heart rate has the interest of cardiologists, because a rise is generally not a good thing. With liraglutide, heart rate increased with a few beats per minute, but this did not cause any harm. And the beneficial effects of liraglutide were seen despite this small increase in heart rate.

In summary, liraglutide showed an absolute risk reduction in the three-point MACE of 1.9% and a relative reduction of 13%. CV death was reduced by 22%, all-cause death by 15%, microvascular complications by 16% and renal complications by 22%.

Now turning to the SUSTAIN 6 study that evaluated semaglutide [27], we can see that the patient population was quite similar to the one in LEADER. While the primary endpoint also showed a decrease in SUSTAIN 6, here this was mostly due to reductions in non-fatal MI and stroke, with little effect on CV death. MI, stroke, and the necessity for revascularization, all events related to atherosclerosis or progression thereof, were favorably impacted by semaglutide, while heart failure and mortality were not. Thus, these outcomes may reflect a decrease in the progress of atherosclerosis rather than any immediate effect of semaglutide. The study was not very long, thus it may take longer to show an effect on mortality.

Retinopathy was actually increased in the semaglutide group in SUSTAIN 6. Combining this observation with the LEADER findings, there is an indication that retinopathy may be increased with GLP-1RA. It may relate to the immediate, quite substantial improvement in glycemic control, which is known in people with established retinopathy to deteriorate the condition. A huge meta-analysis [30] in an American insurance database compared incretins, DPP-4 inhibitors, and GLP-1RA with regard to retinopathy. That analysis gave no indication that these incretins increase retinopathy.

Semaglutide did not cause hypoglycemia, the side effect that gets most of the attention. Pancreatitis and pancreatic cancer were not increased in any of these studies with tens of thousands of patients.

A remaining question is why these differences are seen between GLP-1RA trials. Differences in study populations may play a role: ELIXA was conducted in patients with T2DM and recent acute coronary syndrome, and the proportion of patients with CVD and only CV risk factors differs. The REWIND trial, evaluating dulaglutide, which will be published in June in 2019, has a low proportion of people with established CVD compared to the other trials [31]. Another factor may be use of non-study medications, different dosing of other therapies, and difference in glycemic control. For instance, glycemic control with semaglutide was somewhat better than with liraglutide or other GLP-1RAs. The GLP-1RA backbone may also play a role, with the exendin-4-based differing from the human analogs, as may the duration of action. The molecular structure of different GLP-1RAs and their half-life vary considerably. The GLP-1RAs that have shown positive results in the outcome trials are more human-like and have a long duration of action.

Another remaining question is whether GLP-1RAs will be effective in less ill patients, so the results of REWIND are of great interest. PIONEER-6 will provide insights on an oral form of semaglutide, which is currently being tested in people with impaired glucose tolerance, prediabetes. Semaglutide is also being tested in obese people (SELECT study) with CVD manifestations but without diabetes, with the hypothesis that we could reduce CV events.

The impact these studies have had on guidelines is considerable and vast. Many recently updated T2DM guidelines worldwide included therapy with GLP-1RAs, because the world really loved to see drugs that could improve the prognosis in people with diabetes. Ongoing studies will further inform us on the use of these agents.

References

Show references

29. Madsbad S et al., Diabetes Obes Metab 2011; 13:394–407

30. Bethel et al., Lancet Diabetes Endocrinol. 2018; 6:105

31. Gerstein HC et al., Diabetes Obes Metab 2017;20:564-570

Educational information

This is a summary of the presentation given by Lars Rydén, during the PACE symposium entitled 'Outcomes of GLP-1 RA in Diabetes & CVD: What are the key opportunities for cardiology practice?', held during ESC in Munich, Germany, on August 27, 2018.